The present invention relates to regulators for the activation of glycine receptors comprising morphan derivatives or salts thereof. The described regulators potentiate or inhibit the activation of the receptor (glycine receptors) which is specifically bound with the inhibitory neurotransmitter glycine. More particularly, the potentiators for the activation of glycine described in the present invention are useful as drugs for the treatment of convulsive seizures or epileptic seizures and as anesthetics. Further, the inhibitors for the activation of glycine receptors described in the present invention are useful as drugs for the treatment of nonketotic hyperglycinemia, and as antitussives or central nervous system stimulants. The regulators for the activation of glycine receptors described in the present invention are also useful as pharmacological tools for analyzing the function of these receptors.
The present invention also relates further to the medicinal compositions containing morphan derivatives represented by the formula (1) or salts thereof and pharmaceutically acceptable carrier thereof. Further, the present invention relates to novel compounds comprising morphan derivatives or salts thereof represented by the formula (2).
Glycine is a major inhibitory neurotransmitter of the central nervous system and is distributed mainly in the medulla and the spinal cord. This is in sharp contrast to another inhibitory neurotransmitter, "Ugr"-aminobutyric acid (GABA), which is distributed in the upper central region. With regard to the GABA receptor and the GABAergic neurotransmitter mechanism, a binding site, which is modified by antianxiety drugs, anesthetics, anticonvulsants or hypnotics, acting on the GABA receptor-ionchannel complex (hereinafter designated as the GABA receptor) has been elucidated (Ann. Rev. Neurosci., 17, 569-602, 1994); and drugs targeting the GABA receptor have been developed extensively. The importance of the GABA receptor for maintaining the functions of the psychoneural system has been recognized, and its physiological roles and pharmacological significance, including its regulatory mechanism, have been thoroughly elucidated. On the contrary, with regard to drugs modifying the functions of the glycine receptors, such as the known glycine receptors antagonist, strychnine, only a small number of drugs has been found. Owing to this fact, the pharmacological significance of glycine receptors has not been well elucidated and even their physiological role remains unknown.
With respect to the function and structure of the glycine receptor, in addition to results of studies on the electrophysiological properties of the glycine receptor [Nature, 277, 234-236; Nature, 305, 805-808, 1983; J. Physiol. (Lond.), 385, 243-286, 1987; J. Physiol. (Lond.), 435, 303-331, 1991], the molecular structure of glycine receptors has been estimated. This has been accomplished as a result of introducing molecular biological studies [J. Physiol. (Paris), 88, 243-248, 1994; Curr. Opin. Neurobiol., 5, 318-323, 1995], and the actual features of the glycine receptor as a functional molecule have been determined. Based on these findings, the relationship between the glycine receptor and nervous diseases has recently been elucidated from the clinical standpoint. For example, it has been reported that the causes of diseases resulting in convulsive symptom in glycine receptors deficient mice (Nature, 298, 655-657, 1982) and familial xe2x80x9cstartle diseasexe2x80x9d are both due to mutations in the gene coding for the glycine receptors (J. Biol. Chem., 269, 18739-18742, 1994; Trends Neurosci., 18, 80-82, 1995). Since these nervous system diseases are caused by functional disorders in the glycine receptors in the central nervous system networks, drugs which can potentiate the activation of the glycine receptors, help them to recover the original networks of the central nervous system. This is done by activating the remaining small numbers of normally functioning glycine receptors more strongly in vivo. As a result, this is expected to ameliorate or treat the symptoms of nervous diseases.
An example of another nervous diseases involving the glycine receptors is nonketotic hyperglycinemia, which is a fatal idiopathic abnormal metabolic disease (The Metabolic Basis of Inherited Diseases, McGraw-Hill, N.Y., pp. 743-753, 1989). Nonketotic hyperglycinemia is characterized by the accumulation of glycine in the blood and cerebrospinal fluid, which is caused by a defect in an enzyme of the glycine cleavage system. It is a disease resulting in a severe nervous disorder as a result of hyperactivation of the glycine receptors. Heretofore, drugs which suppress the activation of glycine receptors have been expected to reduce the neurotoxicity induced by glycine. Clinical cases in which the above-mentioned strychnine has been applied as a drug for treatment of such diseases have been reported (Helv. Paediat. Acta, 32, 517-525, 1977; Pediatrics, 63, 369-373, 1979; Helv. Paediat. Acta, 34, 589-599, 1979). However, massive doses of strychnine produce strong systemic toxicity, and small doses of strychnine also result in toxic symptoms, as well as accumulation. It is a drug which is very difficult to use in clinical practice. Consequently, the development of very safe activation inhibitors as alternatives to strychnine is strongly desired.
Further, recent reports on the relationships between glycine receptors and central nervous system agonists have attracted attention. Firstly, it has been demonstrated that a known inhalation general anesthetic agent, enflurane, recognizes a specific amino acid residues in the glycine receptors and potentiates the activation of the receptor (Nature, 389, 385-389, 1997). Since the mechanism of action of anesthetic agents has been said to be a non-selective action such as affecting the fluidity of the nerve cell membrane, knowledge about regulation of the activation by binding the anesthetic agent with the receptor suggests the fact that this is an action against a target with high specificity in the central nervous system. Consequently, drugs which can potentiate the activation of glycine receptors are expected to be candidates for anesthetic agents. Secondly, it has been reported that a common mechanism of action of large numbers of central antitussives, such as dextromethorphan, is to suppress the activation of glycine receptors (Br. J. Pharmacol., 120, 690-694, 1997; Meth. Find. Exp. Clin. Pharmacol., 20, 125-132, 1998). Antitussives are developed to provide remission or suppression of the pathologic cough which accompanies the pathological conditions of respiratory diseases; and, at present, large numbers of narcotic and nonnarcotic central antitussives are used as drugs. However, even though the former have strong antitussive action, their use is limited due to their narcotic action, and the latter produce insufficient antitussive effects. Consequently, the development of ideal antitussives with fewer adverse effects and sufficient efficacy is strongly desired; and inhibitors of the activation of glycine receptors are expected to be candidate drugs for antitussives with reliable effects.
In addition, agents developed as drugs can be utilized as pharmacological tools, and are used for analyses of mechanisms of regulation of various receptors or ion channels. Further, the strychnine mentioned above has been commonly used only for analyses of function of the glycine receptor. Consequently, drugs for regulating the activation of the glycine receptors are expected to be a useful pharmacological tool in order to understand the regulatory mechanisms of the physiological roles of these receptors.
A known example of a morphan derivative is the five-membered ring morphine and immunosuppressant FR901483. Various morphan derivatives have been reported as a result of studies on the synthesis of these compounds. For example, N. Yamazaki, et al., J. Org. Chem., 62, 8280-8281, 1997, describe the synthesis of 1-lower alkyl-morphan derivatives.
As explained above, knowledge that the glycine receptors is involved in neurological diseases, and that known drugs have a mechanism of action for regulating the function of glycine receptors, indicates that the glycine receptors is a hopeful new target for drug development, as well as for development of drugs having novel mechanisms of action. In addition, if drugs modifying the function of glycine receptors can be developed, completely new therapeutic methods for various neurological diseases can be provided.
Consequently, the present invention results in morphan derivatives which are useful as novel regulators for the activation of glycine receptors.
The present inventors conducted thorough investigation to solve the above described problems, and found for the first time that morphan derivatives or salts thereof, in particular, morphan derivatives (2-azabicyclo[3.3.1]nonane derivatives) or salts thereof represented by the formula (1) potentiate or inhibit the activation of glycine receptor, and have completed the present invention.
Thus, the present invention relates to a medicinal composition containing morphan derivatives or salts thereof having a regulating action for the activation of glycine receptor and pharmaceutically acceptable carrier thereof, methods of treatment for various diseases caused by disorder of the activation of glycine receptor by using the above described medicinal compositions and use of morphan derivatives or salts thereof to produce the above medicinal composition.
In more detail, the present invention relates to medicinal compositions containing morphan derivatives or salts thereof represented by the following formula (1) and pharmaceutically acceptable carrier thereof: 
wherein, R1 shows a hydrogen, an optionally substituted lower alkyl group, an optionally substituted alkenyl group, an optionally substituted aromatic aliphatic group or an alkylene group having an optional substitution group which can form a ring together with adjacent atoms and R2; and,
R2 shows a hydrogen, an optionally substituted lower alkyl group or an optionally substituted alkenyl group.
In further more detail, the present invention relates to drugs to regulate the activation of glycine receptor, containing morphan derivatives or salts thereof. The present invention also relates to morphan derivatives or salts thereof represented by the following formula (2) or salts thereof: 
wherein, R1 shows a hydrogen, an optionally substituted lower alkyl group, an optionally substituted alkenyl group, an optionally substituted aromatic aliphatic group or an alkylene group having an optional substituent which can form a ring together with adjacent atoms and R2; and,
R2 shows a hydrogen, an optionally substituted lower alkyl group or an optionally substituted alkenyl group;
however, R2 is not a hydrogen or an unsubstituted lower alkyl group when R1 is a hydrogen, and a substituent on a lower alkyl group, an alkenyl group and an aromatic aliphatic group in R1 and R2 is not a hydroxyl group, and is not a propylene group when R1 is an alkylene group.
The present invention further relates to medicinal compositions containing morphan derivatives or salts thereof and pharmaceutically acceptable carrier thereof, having an regulating action for the activation of glycine receptor or having a central nervous action, use of morphan derivatives or salts thereof represented by the above formula (2) to produce the above described medicinal compositions having a regulating action for the activation of glycine receptor or having a central nervous action, and also methods for treatment or prevention of diseases caused by disorder of the activation of glycine receptor, preferably diseases on central nervous system, comprising administrating an effective amount of a morphan derivative or a salt thereof represented by the above described formula (2).